The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors
The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors
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DOI：
10.1093/nar/27.11.2291
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发表时间：
1999-06-01
影响因子：
14.9
通讯作者：
Jones, PA
中科院分区：
文献类型：
--
作者：
Robertson, KD;Uzvolgyi, E;Jones, PA
哺乳动物的DNA甲基化是胚胎发育、X染色体失活和印记所必需的。先前的研究表明，甲基化模式在恶性细胞中变得异常，并且可能通过不适当的从头甲基化和生长调节基因启动子的沉默而导致肿瘤发生。DNA甲基转移酶DNMT 1的RNA和蛋白质水平在肿瘤中已经显示出升高，然而缺乏Dnmt 1的鼠干细胞仍然能够从头甲基化病毒DNA。最近在小鼠中克隆了一个新的DNA甲基转移酶家族（Dnmt 3a和Dnmt 3b），其以相同的效率甲基化半甲基化和未甲基化的模板，使它们成为长期寻求的从头甲基转移酶的候选者。我们已经研究了人DNMT 1，3a和3b的表达，并发现在大多数正常组织中所有三种转录物的广泛，协调表达。染色体定位将DNMT3a定位在染色体2p23上，DNMT3b定位在染色体20q11.2上。在肿瘤中观察到DNMT3b的显著过表达，而DNMT1和DNMT3a仅适度过表达且频率较低。最后，几种新的选择性剪接形式的DNMT3b，这可能已经改变了酶活性，被发现以组织特异性的方式表达。
DNA methylation in mammals is required for embryonic development, X chromosome inactivation and imprinting. Previous studies have shown that methylation patterns become abnormal in malignant cells and may contribute to tumorigenesis by improper de novo methylation and silencing of the promoters for growth-regulatory genes. RNA and protein levels of the DNA methyltransferase DNMT1 have been shown to be elevated in tumors, however murine stem cells lacking Dnmt1 are still able to de novo methylate viral DNA, The recent cloning of a new family of DNA methyltransferases (Dnmt3a and Dnmt3b) in mouse which methylate hemimethylated and unmethylated templates with equal efficiencies make them candidates for the long sought de novo methyltransferases. We have investigated the expression of human DNMT1, 3a and 3b and found widespread, coordinate expression of all three transcripts in most normal tissues. Chromosomal mapping placed DNMT3a on chromosome 2p23 and DNMT3b on chromosome 20q11.2. Significant overexpression of DNMT3b was seen in tumors while DNMT1 and DNMT3a were only modestly overexpressed and with lower frequency. Lastly, several novel alternatively spliced forms of DNMT3b, which may have altered enzymatic activity, were found to be expressed in a tissue-specific manner.